Abstract
A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.
2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Atherosclerosis / drug therapy
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Binding Sites
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Cell Line
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Computer Simulation
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Humans
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Lipoproteins, LDL / deficiency
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Lipoproteins, LDL / genetics
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Lipoproteins, LDL / metabolism
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Liver X Receptors
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Mice
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Mice, Knockout
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Microsomes / metabolism
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Orphan Nuclear Receptors / agonists*
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Orphan Nuclear Receptors / metabolism
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Quinolines / chemistry*
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Rats
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Structure-Activity Relationship
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Sulfones / chemical synthesis
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Sulfones / chemistry*
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Sulfones / therapeutic use
Substances
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Lipoproteins, LDL
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Liver X Receptors
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NR1H3 protein, human
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Nr1h3 protein, mouse
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Nr1h3 protein, rat
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Orphan Nuclear Receptors
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Quinolines
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Sulfones
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quinoline